The goal of this proposal is to further investigate the hypothesis that CD1d-restricted NKT cells exert a negative regulatory role over MZB cells. This mechanism might play a central role in the maintenance of tolerance, and its deregulation could be involved in triggering or sustaining autoimmunity as suggested by animal models of diabetes and experimental allergic encephalitis (EAE). Preliminary data from Dr. Porcelli's lab indicate that NKT/MZB cell interaction may also play a key role in preventing the development of humoral autoimmunity, such as that which is characteristic of lupus. MZB cells have been shown to be an important source of autoreactive pathogenic antibodies in lupus, and a variety of studies indicate that the NK T cells that may regulate this B cell population is defective in mice that are predisposed to develop SLE. The proposed study will assess the influence of NK T cells on the responses of MZB cells against well characterized T-independent (TI-2) antigens. This approach will allow a detailed series of experiments to investigate the potential role of NKT cells over MZB cells. A series of in vitro and in vivo analyses using TI-2 antigens to challenge C57BL/6 mice will be performed and compared to results in lupus prone mice (NZB/W F1) and NKT deficient (Jalpha281 KO) mice. Finally, it is predicted that NKT cells could prove to be a potential therapeutic target for some autoimmune diseases including lupus, and this hypothesis will be tested by using artificial activators of NKT cells and investigating their effect in MZB activation by T1-2 antigens.